Despite major advances in the HIV prevention toolbox in the past decade, there remain substantial social, economic, and structural barriers to access to preexposure prophylaxis (PrEP) that prevent a universal, population-level reduction in HIV incidence. Daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) has been the flagship PrEP regimen, and data support a pericoital/on-demand "2-1-1" dosing schedule for men who have sex with men. Daily oral PrEP with tenofovir alafenamide combined with emtricitabine (TAF/FTC) was approved by the US Food and Drug Administration (FDA) in 2019 for all routes of exposure other than vaginal exposures. The effectiveness of daily oral TDF/FTC has not been consistent in cisgender women outside of serodifferent couples, likely owing to differences in vaginal tissue penetration of PrEP agents resulting in less "forgiveness" of nonadherence. These observations have highlighted the need for additional choices of HIV prevention strategies. Injectable long-acting cabotegravir was recently shown to be superior to daily oral TDF/FTC across risk populations. PrEP studies of islatravir are underway for a monthly oral formulation and a drug-eluting subdermal implant. Lenacapavir, with a novel mechanism of action, is under investigation as a subcutaneous injection at 6-month intervals.